Aspirin in Primary Prevention of Cardiovascular Disease and Cancer: A Systematic Review of the Balance of Evidence from Reviews of Randomized Trials

Background
Aspirin has been recommended for primary prevention of cardiovascular disease (CVD) and cancer, but overall benefits are unclear. We aimed to use novel methods to re-evaluate the balance of benefits and harms of aspirin using evidence from randomised controlled trials, systematic reviews and meta-analyses.
Methods and Findings
Data sources included ten electronic bibliographic databases, contact with experts, and scrutiny of reference lists of included studies. Searches were undertaken in September 2012 and restricted to publications since 2008. Of 2,572 potentially relevant papers 27 met the inclusion criteria. Meta-analysis of control arms to estimate event rates, modelling of all-cause mortality and L'Abbé plots to estimate heterogeneity were undertaken. Absolute benefits and harms were low: 60-84 major CVD events and 34-36 colorectal cancer deaths per 100,000 person-years were averted, whereas 46-49 major bleeds and 68-117 gastrointestinal bleeds were incurred. Reductions in all-cause mortality were minor and uncertain (Hazard Ratio 0.96; 95% CI: 0.90-1.02 at 20 years, Relative Risk [RR] 0.94, 95% CI: 0.88-1.00 at 8 years); there was a non-significant change in total CVD (RR 0.85, 95% CI: 0.69-1.06) and change in total cancer mortality ranged from 0.76 (95% CI: 0.66-0.88) to 0.93 (95% CI: 0.84-1.03) depending on follow-up time and studies included. Risks were increased by 37% for gastrointestinal bleeds (RR 1.37, 95% CI: 1.15-1.62), 54%-66% for major bleeds (Rate Ratio from IPD analysis 1.54, 95% CI: 1.30-1.82, and RR 1.62, 95% CI: 1.31-2.00), and 32%-38% for haemorrhagic stroke (Rate Ratio from IPD analysis 1.32; 95% CI: 1.00-1.74; RR 1.38; 95% CI: 1.01-1.82).
Conclusions
Findings indicate small absolute effects of aspirin relative to the burden of these diseases. When aspirin is used for primary prevention of CVD the absolute harms exceed the benefits. Estimates of cancer benefit rely on selective retrospective re-analysis of RCTs and more information is needed.

## 背景
阿司匹林被推荐用于心血管疾病（cardiovascular disease, CVD）与癌症的一级预防，但其整体获益尚不明确。本研究旨在借助随机对照试验、系统评价及荟萃分析的证据，采用新颖方法重新评估阿司匹林的获益与风险平衡。

## 方法与结果
本研究的数据来源包括10个电子书目数据库、专家咨询以及对纳入研究参考文献列表的核查。检索于2012年9月开展，且限定为2008年以来发表的文献。在2572篇潜在相关文献中，共有27篇符合纳入标准。本研究开展了对照臂的荟萃分析以估算事件发生率、全因死亡率建模以及采用L'Abbé图（L'Abbé plots）评估异质性。
阿司匹林的绝对获益与风险均较低：每10万人年可避免60~84例主要心血管不良事件与34~36例结直肠癌死亡，而新增46~49例主要出血事件以及68~117例胃肠道出血事件。全因死亡率的降低幅度较小且不确定性较高（20年随访时风险比（Hazard Ratio, HR）为0.96，95%置信区间（confidence interval, CI）：0.90~1.02；8年随访时相对危险度（Relative Risk, RR）为0.94，95%置信区间：0.88~1.00）；总体心血管事件未出现显著变化（RR=0.85，95%置信区间：0.69~1.06），而总体癌症死亡率的变化范围为0.76（95%置信区间：0.66~0.88）至0.93（95%置信区间：0.84~1.03），具体取决于随访时长与纳入的研究。胃肠道出血风险升高37%（RR=1.37，95%置信区间：1.15~1.62），主要出血风险升高54%~66%（个体参与者数据（individual participant data, IPD）分析的率比（Rate Ratio）为1.54，95%置信区间：1.30~1.82，RR为1.62，95%置信区间：1.31~2.00），出血性卒中风险升高32%~38%（IPD分析的率比为1.32，95%置信区间：1.00~1.74；RR为1.38，95%置信区间：1.01~1.82）。

## 结论
研究结果显示，相较于这些疾病的疾病负担，阿司匹林的绝对效应较小。当阿司匹林用于心血管疾病的一级预防时，其绝对风险超过获益。癌症获益的评估依赖于对随机对照试验的选择性回顾性再分析，仍需更多相关数据。